Pharmaceutical composition for external use

ABSTRACT

A pharmaceutical composition for external use, including: i) luliconazole represented by the following structural formula (1) and/or a salt thereof; and ii) crotamiton. 
     (−)-(E)-[(4R)-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imidazolyl acetonitrile

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.12/281,967, filed Sep. 5, 2008 which is the U.S. National Phase under 35U.S.C. §371 of International Application PCT/JP2006/319708, filed Oct.2, 2006, which was published in a non-English language, which claimspriority to JP Patent Application No. 2006-062079, filed Mar. 8, 2006and JP Patent Application No. 2006-215871 filed Aug. 8, 2006. The aboveapplications are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to a pharmaceutical composition forexternal use, and more particularly, to a pharmaceutical composition forexternal use, which can be preserved in a state where a decrease inoptical purity is suppressed.

BACKGROUND ART

The Japanese archipelago extends from a subtropical zone to a temperatezone and has a warm climate high in humidity, which is liable tofacilitate propagation of fungi such as molds. In addition, due towesternization of clothes, people are now accustomed to wearing shoes onfeet. Accordingly, afoot serves as a favorable environment for thepropagation of the fungi, leading to mycotic skin diseases that areserious social issues nowadays. Of those, onychomycosis has a lowcomplete cure rate and high relapsing and reinfection rates. Therefore,an effective therapy has been demanded.

Conventionally, treatments mainly using tolnaftate formulations havebeen conducted on such diseases. In recent years, imidazole-basedantifungal agents, such as bifonazole and itraconazole, are mainly used.

As the imidazole-based antifungal agents, there are commerciallyavailable imidazole-based antifungal agents such as those represented bythe general formula (1) described below, specifically, luliconazolerepresented by the structural formula (1) below and lanoconazolerepresented by the structural formula (2) below. A commerciallyavailable product called “Lulicon” (registered trademark) is alsopresent (e.g., see Patent Document 1 and Patent Document 2).

The luliconazole is an imidazole-based antifungal agent having opticalactivity with a wide antifungal spectrum, in particular, showsremarkable antifungal activity against dermatophytes. In addition, theluliconazole is also characterized in that its retention in the stratumcorneum is extremely high, and thus is a compound expected to be appliedto treatment of onychomycosis. Like other imidazole-based antifungalagents, however, luliconazole and lanoconazole are agents havingproblems in their solubility, so there is a need of using a solvent fortheir preparation. On the other hand, in some cases, the characteristicfeatures of luliconazole may include a risk of a decrease in its opticalpurity when it is stored in a dissolved state under severe circumstancesdue to a type of a solvent used for dissolution, temperature, acid andbase, or the like. Besides, such a decrease in optical purity may relateto a solvent. In other words, with regard to a pharmaceuticalcomposition for external use containing luliconazole and/or a saltthereof, it is desirable to provide means for increasing the solubilitythereof while suppressing a decrease in optical purity even under severeenvironment.

A decrease in optical purity is a common phenomenon, which sometimesoccurs in an optically active compound according to storage conditions,particularly under severe conditions at high temperature. However, nomeans for suppressing the phenomenon is known.

Heretofore, in a pharmaceutical technology for antifungal agents,various studies have been conducted for increasing the solubilitythereof (see, for example, Patent Documents 3 to 5). However, theantifungal agents to be dissolved show increases different in theirsolubility. Therefore, the effect of one of them cannot be directlyapplied to the other compounds. Among the solvents, a solvent that actsto prevent the optically active compound from a decrease in opticalpurity has not yet been known.

On the other hand, as a pharmaceutical preparation containingluliconazole and/or a salt thereof, a pharmaceutical preparationcontaining a film-forming agent and a polyoxypropylene/polyoxyethylenecopolymer has been known (see, for example, Patent Document 6), but onecontaining N-methyl-2-pyrrolidone, propylene carbonate, or crotamitonhas not been known at all. In addition, a basic process formanufacturing an imidazole-based compound is also already known in theart (see, for example, Patent Document 7):

General formula (1)where X represents a hydrogen atom or a chloride atom.

-   Patent Document 1: JP 10-226686 A-   Patent Document 2: JP 2-275877 A-   Patent Document 3: JP 5-306223 A-   Patent Document 4: JP 7-206711 A-   Patent Document 5: WO96/11710-   Patent Document 6: WO03/105841-   Patent Document 7: JP 62-93227 A

DISCLOSURE OF THE INVENTION Problem to be Solved by the Invention

The present invent has been made under such circumstances, and an objectof the present invention is to provide a technique of dissolvingluliconazole and/or a salt thereof (hereinafter, also referred to as“luliconazole or the like”) and preserving the luliconazole or the likein a state where a decrease in optical purity is suppressed.

Means for Solving the Problem

In consideration of such a situation, the inventors of the presentinvention have made intensive studies and efforts to obtain a techniqueof dissolving luliconazole and/or a salt thereof and pre serving theluliconazole or the like in a state where a decrease in optical purityis suppressed and have finally completed the present invention byfinding out that the luliconazole or the like can be stored in a statewhere a decrease in optical purity thereof is suppressed in addition toincrease the solubility of the luliconazole or the like by dissolvingthe luliconazole or the like in an organic solvent, such asN-methyl-2-pyrrolidone, propylene carbonate, or crotamiton. In otherwords, the present invention is as follows:

(1) A pharmaceutical composition for external use, including: i)luliconazole represented by the following structural formula (1) and/ora salt thereof; and ii) one or two or more selected fromN-methyl-2-pyrrolidone, propylene carbonate, and crotamiton.

(2) A pharmaceutical composition for external use according to the item(1), in which the pharmaceutical composition for external use isprovided for treatment or prevention of onychomycosis.

Effects of the Invention

According to the present invention, a pharmaceutical composition forexternal use to be stored in a state in which luliconazole or the likeis dissolved and prevented from a decrease in optical purity thereof canbe provided.

BEST MODE FOR CARRYING OUT THE INVENTION

(1) Luliconazole and/or a Salt Thereof as Essential Components of aPharmaceutical Composition for External Use (Hereinafter, Referred to asPharmaceutical Composition of the Present Invention)

The pharmaceutical composition for external use of the present inventioncontains as essential components luliconazole and/or a salt thereof. Theabove-mentioned luliconazole is represented by the above-mentionedstructural formula (1). The above-mentioned luliconazole is a knowncompound represented by(−)-(E)-[(4R)-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imidazolylacetonitrile. Its manufacturing method and the antifungal properties arealready known in the art. JP 62-93227 A (Patent Document 7 above) can beused as reference.

In addition, “salt thereof” is not specifically limited as far as it isphysiologically acceptable. Preferable examples thereof include: mineralacid salts such as hydrochloride, nitrate, sulfate, and phosphate;organic acid salts such as citrate, oxalate, lactate, and acetate; andsulfuric acid-containing salts such as mesilate and tosilate. In termsof safety and solubility, hydrochloride is more preferable.

In the pharmaceutical composition for external use of the presentinvention, the content of luliconazole or the like is preferably 0.1 to30% by mass, more preferably 0.5 to 15% by mass in total with respect tothe total amount of the pharmaceutical composition. The content ofluliconazole or the like can be determined based on its solubility andformulation characteristics.

(2) Essential Component of Pharmaceutical Composition for external useof the present invention: N-methyl-2-pyrrolidone, propylene carbonate,or crotamiton

The pharmaceutical composition for external use of the present inventioncontains one or two or more organic solvents selected fromN-methyl-2-pyrrolidone, propylene carbonate, and crotamiton as anessential component. Obviously, for the organic solvent, there may beused a single kind thereof or a combination of two or more kindsthereof. In the pharmaceutical composition of the present invention,among the above organic solvents, it is preferable to contain at leastN-methyl-2-pyrrolidone, particularly both N-methyl-2-pyrrolidone andpropylene carbonate. The organic solvent of such a preferable aspect isexcellent not only in action of dissolving luliconazole or a saltthereof but also in action of suppressing, in a dissolved state, adecrease in optical purity. For exerting such an action sufficiently,the total content of such a solvent is preferably 0.1 to 40% by mass,more preferably 1 to 10% by mass with respect to the total amount of thepharmaceutical composition.

(3) Pharmaceutical Composition for External Use of the Present Invention

The pharmaceutical composition for external use of the present inventioncan contain any of components commonly used in pharmaceuticalcompositions in addition to those described above, as far as it does notimpair the effects of the present invention.

Preferable examples of such components include: hydrocarbons such asvaseline and microcrystalline wax; esters such as jojoba oil andcetaceum; triglycerides such as beef tallow and olive oil; higheralcohols such as cetanol and oleyl alcohol; fatty acids such as stearicacid and oleic acid; alcohols such as ethanol and isopropanol;polyalcohols such as glycerin and 1,3-butanediol; water; non-ionicsurfactants; anionic surfactants; cationic surfactants; amphotericsurfactants; thickeners such as polyvinyl pyrrolidone and carbopol;preservatives; UV absorbers; antioxidants; pigments; and powders. Thoseoptional components and the above-mentioned component are treated bycommon procedures, whereby a pharmaceutical composition for external useof the present invention can be produced. The pharmaceutical compositionfor external use of the present invention is not specifically limited asfar as it is formulated into any of forms used for pharmaceuticalcomposition for external uses, and preferable examples thereof includelotions, emulsions, gelatinizing agents, cream pharmaceuticals,aerosols, nail enamel agents, and hide gel patches. Of those, thelotions are most preferable. For stabilizing the clarity and color ofsolution such as luliconazole, 50 to 90% by mass of ethanol is mostpreferably contained.

The pharmaceutical composition for external use of the present inventionis preferably used for treating mycotic diseases or preventingprogression of the diseases by using characteristics of luliconazole orthe like. The mycotic diseases include: foot trichophytosis such asathlete's foot; trichophytosis corporis such as candida and pityriasisversicolor; and trichophytosis on a hard keratin portion, such asonychomycosis. Because of remarkable effects, it is particularlypreferable to use the pharmaceutical composition for external use of thepresent invention for treating the hard keratin portion, such asonychomycosis. In particular, the pharmaceutical composition forexternal use of the present invention exerts preferable effects on thenail and such an effect is also exerted on typical dermatomycosis.Therefore, the application of a pharmaceutical composition for externaluse against dermatomycosis, which satisfies the configuration of thepresent invention, is also within the technical scope of the presentinvention. Examples of such dermatomycosis include trichophytosis suchas foot trichophytosis, particularly horny-outgrowing typehyperkeratotic trichophytosis which appears on heels or the like. Thepresent invention has a significant effect on the horny-outgrowing typehyperkeratotic trichophytosis, on which the conventional agents hardlyexert their effects, among the above-mentioned dermatomycosis, which ispreferable.

With regard to its use, for example, the pharmaceutical composition isapplied on a diseased portion one or several times a day and thetreatment is preferably carried out day after day. In particular, foronychomycosis, luliconazole or the like, which is an effective componentin an amount that cannot be attained by normal formulation, can betransferred into the nail. Therefore, onychomycosis can be treated onlyby the external application without having to drink an antifungal agentover a long period of time. In addition, recurrence and reinfection havebeen a major problem for onychomycosis. However, the recurrence andreinfection can be prevented by application of the pharmaceuticalcomposition for external use of the present invention for 1 to 2 weeksafter abatement of the symptom. Therefore, the pharmaceuticalcomposition for external use of the present invention exerts preventiveefficacy in this aspect.

EXAMPLES

Hereinafter, the present invention will be described in more detail withreference to examples. However, the present invention is not limited tothose examples.

Examples 1 to 6 and Comparative Examples 1 to 4

According to the formulation shown in Table 1, PharmaceuticalPreparations 1 to 6 each containing the pharmaceutical composition forexternal use of the present invention were prepared. That is,formulation components were stirred at room temperature and componentsfor pharmaceutical preparation were then dissolved, thereby obtaining apharmaceutical preparation of a clear lotion dosage form. Here, thevalue represents “% by mass”. Likewise, according to Table 2,Comparative Pharmaceutical Preparations 1 to 4 for the respectivecomparative examples were also prepared.

TABLE 1 Pharmaceutical Preparations 1 2 3 4 5 6 Luliconazole 1 1 1 1 1 1N-methyl-2-pyrrolidone 5 8 5 8 Propylene carbonate 5 10 Crotamiton 5Squalane 5 1,3-butylene glycol 20 25 Concentrated glycerin 3 Cetanol0.75 POE (10) hydrogenated castor oil 1 POE (10) lauric acid 0.25Stearic acid monoglyceride 0.25 Water 10 55.75 Ethanol 94 94 94 81 64

TABLE 2 Comparative Pharmaceutical Preparations 1 2 3 4 Luliconazole 1 11 1 Dimethyl sulfoxide 5 Methyl ethyl ketone 5 Ethyl acetate 5 Ethanol94 94 94 99

Experimental Examples

Pharmaceutical Preparations 1 to 6 and Comparative PharmaceuticalPreparations 1 to 4 as described above were subjected to two-weekstorage experiments under conditions of 40° C. and 60° C. Immediatelybefore and after the storage experiment, the amount of an SE body((S)-(+)isomer) produced, which is an enantiomer of luliconazole, wasmeasured by HPLC and expressed in area percentage to investigate thestability thereof. The results are shown in Table 3. Consequently, itcan be recognized that any of the pharmaceutical composition forexternal uses of the present invention is stored in a state where adecrease in optical purity is suppressed.

<HPLC Conditions>

-   -   Instrument used: LC-97 system (Shimadzu Corporation)    -   Column: CHIRALPACK AD-H 4.6 mm×250 mm    -   Column temperature: 40° C.    -   Mobile phase: Water:acetonitrile=90:11 to 60:40 (30-minute        gradient condition)    -   Flow rate: 0.8 ml/min    -   Detection: UV (300 nm in wavelength)    -   Quantitative assay: an area-percentage method using an absolute        working curve

TABLE 3 Stability (Increased amount of SE isomer) At start 40°, 2 Week60°, 2 Week Pharmaceutical 0.16 1.11 3.03 preparation 1 Pharmaceutical0.21 2.13 14.89 preparation 2 Pharmaceutical 0.15 0.55 5.79 preparation3 Pharmaceutical 0.14 0.18 Not detected preparation 4 Pharmaceutical0.44 0.52 Not detected preparation 5 Pharmaceutical 0.32 0.43 Notdetected preparation 6 Comparative 0.20 5.09 23.01 preparation 1Comparative 0.23 8.69 32.73 preparation 2 Comparative 0.19 3.30 31.15preparation 3 Comparative 0.16 8.70 41.68 preparation 4

INDUSTRIAL APPLICABILITY

According to the present invention, a pharmaceutical composition forexternal use to be stored in a state where luliconazole or the like isdissolved and a decrease in optical purity thereof is suppressed can beprovided.

What is claimed is:
 1. A pharmaceutical composition for external use,comprising: i) (R)-luliconazole represented by the following structuralformula (1) and/or a salt thereof; and ii) crotamiton at a concentrationof 0.1 to 40% by mass

(−)-(E)-[(4R)-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imidazolylacetonitrile Structural formula (1).
 2. A pharmaceutical compositionaccording to claim 1, wherein the composition comprises crotamiton in anamount of 1 to 10% by mass of the composition.
 3. A pharmaceuticalcomposition according to claim 1, wherein the composition comprises(R)-luliconazole in an amount of 0.5 to 15% by mass of the composition.4. A pharmaceutical composition according to claim 1, wherein thecomposition further comprises ethanol.
 5. A pharmaceutical compositionaccording to claim 4, wherein the composition comprises ethanol inamount of 50 to 90% by mass of the composition.
 6. A method of treatingmycotic disease comprising externally administering the composition ofclaim 1 to an individual in need of treatment.
 7. A method according toclaim 6, wherein the mycotic disease is foot trichophytosis,trichophytosis corporis or trichophytosis on a hard keratin portion. 8.A method according to claim 6, wherein the mycotic disease is athlete'sfoot.
 9. A method according to claim 6, wherein the mycotic disease isonychomycosis.
 10. A method according to claim 6, wherein the mycoticdisease is a mycotic disease of a nail.
 11. A method according to claim6, wherein the mycotic disease is dermatomycosis.
 12. A pharmaceuticalcomposition according to claim 2, wherein the composition comprises(R)-luliconazole in an amount of 0.5 to 15% by mass of the composition.13. A pharmaceutical composition according to claim 2, wherein thecomposition further comprises ethanol.
 14. A pharmaceutical compositionaccording to claim 13, wherein the composition comprises ethanol inamount of 50 to 90% by mass of the composition.
 15. A pharmaceuticalcomposition according to claim 3, wherein the composition furthercomprises ethanol.
 16. A pharmaceutical composition according to claim15, wherein the composition comprises ethanol in amount of 50 to 90% bymass of the composition.
 17. A pharmaceutical composition according toclaim 12, wherein the composition further comprises ethanol.
 18. Apharmaceutical composition according to claim 17, wherein thecomposition comprises ethanol in amount of 50 to 90% by mass of thecomposition.
 19. A pharmaceutical composition for external use,consisting essentially of: i)(R)-(−)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-iliden]-1-imidazolylacetonitrile and/or a salt thereof; and ii) crotamiton at aconcentration of 0.1 to 40% by mass.
 20. The pharmaceutical compositionof any one of claims 1, 2, 3, 4, 12, or 14, wherein the pharmaceuticalcomposition is formulated as a lotion.